Liquid nimodipine compositions

ABSTRACT

Liquid compositions comprising nimodipine having improved nimodipine concentrations are provided herein. Methods of improving neurological outcome by reducing the incidence and severity of ischemic deficits in patients with subarachnoid hemorrhage from ruptured intracranial berry aneurysms with the liquid compositions of the present invention are also detailed herein.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U.S. patent applicationSer. No. 17/530,728, filed Nov. 19, 2021; which is a continuation ofU.S. patent application Ser. No. 16/722,513, filed Dec. 20, 2019, nowU.S. Pat. No. 11,207,306; which is a continuation of U.S. patentapplication Ser. No. 16/407,980, filed May 9, 2019, now U.S. Pat. No.10,576,070; which is a continuation of U.S. patent application Ser. No.15/954,357, filed Apr. 16, 2018, now U.S. Pat. No. 10,342,787; whichclaims the benefit of U.S. Provisional Application No. 62/621,953, filedJan. 25, 2018, the contents of which are incorporated by reference intheir entirety.

FIELD OF THE INVENTION

The present invention relates generally to liquid nimodipinecompositions with improved stability compared to existing aqueouscompositions comprising nimodipine. The present invention also generallyrelates to methods of treating conditions for which nimodipine isindicated comprising administering the liquid nimodipine composition toa patient in need thereof.

BACKGROUND OF THE INVENTION

Nimodipine is a dihydropyridine derivative calcium channel blockerindicated for the improvement of neurological outcome by reducing theincidence and severity of ischemic deficits in patients withsubarachnoid hemorrhage (SAH) from ruptured intracranial berry aneurysmsregardless of their post-ictus neurological condition (i.e., Hunt andHess Grades I-V). Nimodipine has the chemical name1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate andthe structure shown below:

NIMOTOP® (Bayer Pharmaceuticals Corp.) is a liquid-filled capsuleformulation of nimodipine for oral dosing. Each NIMOTOP® capsulecontains 30 mg of nimodipine and is commonly administered in atwo-capsule 60 mg dose.

The prescribing information for NIMOTOP® states that, if the capsulecannot be swallowed (e.g., at the time of surgery) or if the patient isunconscious, a hole should be made in both ends of the capsule with an18 gauge needle, and the contents of the capsule extracted into asyringe. To help minimize administration errors, it is recommended thatthe syringe be labeled “Not for IV Use”. The contents should then beemptied into the patient's in situ naso-gastric tube and washed down thetube with 30 mL of normal saline (0.9%).

In addition to this method of delivery being cumbersome and timeconsuming, it is also dependent on the ability of the particularpractitioner. It is possible that the practitioner extracts less thanthe full amount of the liquid dose from the capsule, leading to underdosing and insufficient treatment.

NYMALIZE® (Arbor Pharmaceuticals, LLC) was the first marketed oralnimodipine solution, eliminating the need for needle extraction ofnimodipine from capsules for patients that cannot consume capsules.NYMALIZE® is supplied in bottles that should be stored between 20° C. to25° C. (68° F. to 77° F.), protected from light, and un-refrigerated.The recommended dose is 20 mL (containing 60 mg of nimodipine) every 4hours for 21 consecutive days. The inactive ingredients in NYMALIZE® areethanol, glycerin, methylparaben, polyethylene glycol, sodium phosphatemonobasic and water (about 20% by volume).

It has been found that NYMALIZE® slowly degrades under certainconditions (e.g., elevated temperature and humidity). One of thedegradants includes nimodipine related compound A, (2-Methoxyethyl1-methylethyl 2,6-dimethyl-4-(3-nitrophenyl)pyridine-3,5-dicarboxylate)having the following structure:

Accordingly, there remains a need for liquid nimodipine formulationswith improved stability and decreased degradation.

SUMMARY OF THE INVENTION

In one aspect, the present invention generally relates to novel liquidpharmaceutical compositions containing nimodipine that have improvedshelf-life and decreased nimodipine-related degradation compared toexisting liquid pharmaceutical compositions.

In another aspect, the present invention relates to novel liquidcompositions comprising nimodipine in concentrations higher than thoseof other liquid compositions, e.g., NYMALIZE®. The concentration ofnimodipine in NYMALIZE® (60 mg/20 mL) is 3 mg/mL. The liquid compositionof the present invention allows use of a higher nimodipineconcentrations per dose, thereby lowering a patient's daily intake ofthe liquid composition compared to NYMALIZE®.

In preferred embodiments, the liquid compositions of the presentinvention have a nimodipine concentration of about 6 mg/mL or greater.

In one aspect, the present invention provides a liquid compositioncomprising nimodipine. In one embodiment, the liquid compositioncomprises nimodipine and a solvent comprising ethanol, wherein theethanol is present in the composition in an amount of about 1% or lessby weight.

In still another embodiment, the present invention provides a liquidcomposition comprising nimodipine, wherein about 5% or less nimodipinedegradation is observed over a period of at least three months whenexposed to 40° C. and 75% relative humidity.

In certain embodiments, the present invention provides a liquidcomposition comprising nimodipine, wherein about 4.5% or less nimodipinedegradation is observed over a period of at least three months whenexposed to 40° C. and 75% relative humidity.

In another embodiment, the present invention provides a liquidcomposition comprising nimodipine and about 1.2% or less nimodipinerelated compound A when the composition is exposed to 40° C. and 75%relative humidity over a period of at least three months.

In a particular embodiment, the present invention provides a liquidcomposition comprising nimodipine and about 0.01% to about 1.2%nimodipine related compound A when the composition is exposed to 40° C.and 75% relative humidity over a period of at least three months, andmore particularly, about 0.10% to about 0.8% nimodipine related compoundA.

In one embodiment, the present invention provides a liquid compositioncomprising nimodipine and at least about 90% less nimodipine relatedcompound A than NYMALIZE® when both compositions area exposed to 40° C.and 75% relative humidity over a period of at least three months, andmore particularly, at least about 75% less, at least about 60% less orat least about 50% less nimodipine related compound A than NYMALIZE®.

In one embodiment, the present invention provides a liquid compositioncomprising nimodipine and substantially no nimodipine related compoundA. In one embodiment, the present invention provides a liquidcomposition comprising nimodipine, wherein about 2.0% or less totalimpurities are observed over a period of at least three months whenexposed to 40° C. and 75% relative humidity.

In another embodiment, the present invention provides a liquidcomposition comprising nimodipine, wherein about 1.0% or less totalimpurities are observed over a period of at least three months whenexposed to 40° C. and 75% relative humidity.

In a particular embodiment, the present invention provides a liquidcomposition comprising nimodipine, wherein about 0.01% to about 2.0%total impurities are observed over a period of at least three monthswhen exposed to 40° C. and 75% relative humidity, and more particularly,about 0.1% and about 1.9% total impurities.

In one embodiment, the present invention provides a liquid compositioncomprising nimodipine and at least about 90% less total impurities thanNYMALIZE® when both compositions are exposed to 40° C. and 75% relativehumidity over a period of at least three months, and more particularly,at least about 75% less, at least about 60% less or at least about 50%less total impurities than NYMALIZE®.

In one embodiment, the present invention provides a liquid compositioncomprising nimodipine and substantially no total impurities are observedover a period of at least three months when exposed to 40° C. and 75%relative humidity.

In another embodiment, the present invention provides a liquidcomposition comprising nimodipine and about 0.3% or less nimodipinerelated compound A over a period of at least three months when exposedto 25° C. and 60% relative humidity.

In another embodiment, the present invention provides a liquidcomposition comprising nimodipine and about 0.01% to about 0.3%nimodipine related compound A over a period of at least three monthswhen exposed to 25° C. and 60% relative humidity, or more particularly,about 0.01% and about 0.1% nimodipine related compound A.

In one embodiment, the present invention provides a liquid compositioncomprising nimodipine and at least about 90% less nimodipine relatedcompound A than NYMALIZE® when both compositions are exposed to 25° C.and 60% relative humidity over a period of at least three months, andmore particularly, at least about 85% less, at least about 69% less 75%less, at least about 60% less or at least about 50% less nimodipinerelated compound A than NYMALIZE®.

In a particular embodiment, the liquid composition comprises nimodipineand substantially no nimodipine related compound A when the compositionis exposed to 25° C. and 60% relative humidity over a period of at leastthree months.

In another embodiment, the present invention provides a liquidcomposition comprising nimodipine, wherein about 0.4% or less totalimpurities are observed over a period of at least three months whenexposed to 25° C. and 60% relative humidity. In a particular embodiment,the present invention provides a liquid composition comprisingnimodipine, wherein about 0.01% to about 0.4% total impurities areobserved over a period of at least three months when exposed to 25° C.and 60% relative humidity, and more particularly, about 0.1% and about0.4% total impurities.

In one embodiment, the present invention provides a liquid compositioncomprising nimodipine and at least about 90% less total impuritiesrelated than NYMALIZE® when both compositions are exposed to 25° C. and75% relative humidity over a period of at least three months, and moreparticularly, at least about 85% less, at least about 60% less 75% less,at least about 60% less or at least about 50% less total impurities thanNYMALIZE®.

In one embodiment, the present invention provides a liquid compositioncomprising nimodipine and substantially no total impurities are observedover a period of at least three months when exposed to 25° C. and 60%relative humidity.

In another aspect, the present invention provides a method of treatingdisorders, or symptoms associated with disorders for which nimodipineprovides a therapeutic effect.

In one embodiment, the present invention provides a method of reducingthe incidence and severity of ischemic deficits in patients withsubarachnoid hemorrhage from ruptured intracranial berry aneurysmscomprising administering to a patient in need thereof an effectiveamount of a liquid composition described herein.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to liquid compositions comprisingnimodipine. In some embodiments, the liquid compositions of theinvention have improved stability and decreased degradants compared toexisting liquid pharmaceutical compositions, e.g. NYMALIZE®. In otherembodiments, the liquid compositions have increased nimodipineconcentrations compared to existing liquid pharmaceutical compositions,e.g. NYMALIZE®. When comparisons are made, it is understood to be underthe same or similar conditions.

I. DEFINITIONS

Pharmaceutical compositions and medicaments may be described as mixturesof two or more components “by volume,” which is herein defined as thevolume due to one component divided by the volume of all components ofthe pharmaceutical composition. This ratio may be converted to orreported as a percentage of the total composition volume. Such aquantity may also be indicated by “v/v” or “percent v/v.” Similarly, thephrase “by weight” describes the weight due to one component divided bythe weight of all components of the composition. This ratio may beconverted to or reported as a percentage of the total compositionweight. Such a quantity may also be indicated by “w/w” or “percent w/w.”

As used herein, the term “degradation product” refers to impuritiesresulting from chemical changes that occur during drug manufacturing,storage and/or transportation in response to changes in light,temperature, pH, and humidity, or due to inherent characteristics of theactive pharmaceutical substance, such as their reaction with excipientsor on contact with the packaging. For example, the degradation productsof nimodipine include: (1) 2-methoxyethyl1-methylethyl-2,6-dimethyl4-(3-nitrophenyl) pyridine-3,5-dicarboxylate(i.e., nimodipine related compound A); (2) bis(1-methylethyl)-2,6-dimethyl-4-(3-nitrophenyl),1,4-dihydro-pyridine-3,5-dicarboxy-late and (3) bis(2-methoxyethyl)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate.

As used herein, the term “dosage unit” or “unit dose” (usedinterchangeably) refers to one dose of the liquid composition of thepresent invention, as administered to the patient. For example, multipledosage units can be present when the liquid composition of the presentinvention is stored in a bottle. A fraction of that bottle, i.e. asingle dosage unit, is administered to the patient at a time. In thecurrent NYMALIZE® formulation, a dosage unit is 20 mL (containing 60 mgof nimodipine).

As used herein, the term “effective amount” refers the amount of activeagent present in the composition that is needed to provide a desiredlevel of active agent in the bloodstream or the target tissue. Theprecise amount will depend upon numerous factors and can readily bedetermined by one skilled in the art, based upon the informationprovided herein and available in the relevant literature.

As used herein, the term “nimodipine” includes the racemate, othermixtures of (+)- and (−)-isomers, and single enantiomers, but may bespecifically set forth as the racemate, (+)-isomer, (−)-isomer, or anymixture of both (+)- and (−)-isomers. As used herein, the term “patient”refers to a living organism suffering from or prone to a condition thatcan be prevented or treated by administration of a composition describedherein, and includes both humans and animals. In one embodiment, thepatient is a human patient.

As used herein, the terms “pharmaceutically acceptable excipient” or“pharmaceutically acceptable carrier” refers to an excipient that can beincluded in the compositions of the invention and that causes nosignificant adverse toxicological effects to the patient to which thecomposition is administered.

As used herein, the term “stable” or “stabilized” with respect to acomposition is one in which the active ingredient retains its chemicalstability, physical stability, microbiological stability, therapeuticstability and/or toxicological stability. Stability may be measuredunder a variety of conditions including long-term stability,intermediate stability, accelerated stability, real-time stability or acombination thereof. In real-time stability testing, a product is storedat recommended storage conditions and monitored until it fails thespecification. In accelerated stability tests, a product is stored atelevated stress conditions (such as temperature, humidity, and pH).Degradation at the recommended storage conditions can be predicted usingknown relationships between the acceleration factor and the degradationrate.

As used herein, the term “substantially no nimodipine related compoundA” refers to an undetectable amount of nimodipine related compound A asmeasured by HPLC.

As used herein, the term “treat” or “treating” of a disease stateincludes: 1) inhibiting the disease state, i.e., arresting thedevelopment of the disease state or its clinical symptoms; 2)attenuating the disease state, i.e. reducing the number or intensity ofone or more symptoms associated with the disease state, such that one ormore symptoms is reduced but may, or may not be completely eliminated;and/or 3) relieving the disease state, i.e., causing temporary orpermanent regression of the disease state or its clinical symptoms.

II. COMPOSITIONS

In another embodiment, the present invention provides liquidcompositions comprising nimodipine and a solvent system comprising waterand one or more additional solvents. The amount of water in the solventsystem from about 1% to about 25% (w/v), such as, for example, fromabout 1% to less than about 20%, from about 1% to about 15%, from about1% to about 10%, from about 1% to 5%, from about 3% to less than about20%, from about 3% to about 15%, from about 3% to about 10%, from about3% to about 5%, from about 5% to less than about 20%, from about 5% toabout 15%, from about 5% to about 10%, from about 7% to less than about20%, from about 7% to about 15%, from about 7% to about 10%, from about10% to less than about 20%, from about 10% to about 15%, or from about15% to less than about 20%.

Exemplary solvents include, but are not limited to, water, glycerol,dimethylsulfoxide, N-methylpyrrolidone, dimethyl acetamide (DMA),dimethyl formamide, glycerol formal, ethoxy diglycol, triethylene glycoldimethyl ether, triacetin, diacetin, corn oil, acetyl triethyl citrate(ATC), ethyl lactate, polyglycolated capryl glycerides butyrolactone,dimethyl isosorbide, benzyl alcohol, ethanol, isopropyl alcohol,polyethylene glycol of various molecular weights, including but notlimited to PEG 300 and PEG 400, or propylene glycol, or a mixture of oneor more thereof.

In one embodiment, the liquid composition solvent system comprises PEGand at least one protic solvent selected from the group consisting ofethanol, glycerin, water, and combinations thereof. In such embodiments,PEG comprises at least about 50% (w/v) of the solvent system, such, as,for example, at least about 55%, at least about 60%, at least about 65%,at least about 70%, at least about 75%, at least about 80%, at leastabout 85% or at least about 90%. In other embodiments, PEG comprisesfrom about 50% (w/v) to about 90% (w/v) of the solvent system, fromabout 50% (w/v) to about 80% (w/v) of the solvent system, from about 50%(w/v) to about 70% (w/v) of the solvent system, from about 50% (w/v) toabout 60% (w/v) of the solvent system, from about 60% (w/v) to about 90%(w/v), from about 60% (w/v) to about 80% (w/v), from about 60% (w/v) toabout 70% (w/v), from about 70% (w/v) to about 90% (w/v), from about 70%(w/v) to about 80% (w/v), or from about 80% (w/v) to about 90% (w/v).The remainder of the solvent system comprises the at least one proticsolvent selected from the group consisting of ethanol, glycerin, water,and combinations thereof.

In one embodiment, the liquid composition comprises nimodipine and asolvent system comprising water and polyethylene glycol. The amount ofwater in the solvent system can vary from about 1% to about 35% (w/v),such as, for example, from about 1% to about 30%, from about 1% to about25%, from about 1% to about 20%, from about 1% to about 15%, from about1% to about 10%, from about 1% to about 5%, from about 5% to about 35%,from about 5% to about 30%, from about 5% to about 25%, from about 5% toabout 20%, from about 5% to about 15%, from about 5% to about 10%, fromabout 10% to about 35%, from about 10% to about 30%, from about 10% toabout 25%, from about 10% to about 20%, from about 10% to about 15%,from about 15% to about 35%, from about 15% to about 30%, from about 15%to about 25%, from about 15% to about 20%, from about 20% to about 35%,from about 20% to about 30%, from about 20% to about 25%, from about 25%to about 35%, from about 25% to about 30%, or from about 30% to about35%. The amount of polyethylene glycol in the solvent system can varyfrom about 65% to about 99% (w/v), such as, for example, from about 65%to about 95%, from about 65% to about 90%, from about 65% to about 85%,from about 65% to about 80%, from about 65% to about 75%, from about 65%to about 70%, from about 70% to about 99%, from about 70% to about 95%,from about 70% to about 85%, from about 70% to about 80%, from about 70%to about 75%, from about 75% to about 99%, from about 75% to about 95%,from about 75% to about 90%, from about 75% to about 85%, from about 75%to about 80%, from about 80% to about 99%, from about 80% to about 95%,from about 80% to about 90%, from about 80% to about 85%, from about 85%to about 99%, from about 85% to about 95%, from about 85% to about 90%,from about 90% to about 99%, from about 90% to about 95% or from about95% to about 99%. In a particular embodiment, the liquid compositioncomprises nimodipine and a solvent system consisting of water andpolyethylene glycol.

In a particular embodiment, the liquid composition comprises nimodipineand a solvent system comprising from about 1% to about 35% (w/v) waterand from about 65% to about 99% (w/v) polyethylene glycol. In anotherparticular embodiment, the liquid composition comprises nimodipine and asolvent system comprising from about 1% to about 20% (w/v) water andfrom about 80% to about 99% (w/v) polyethylene glycol. In still anotherparticular embodiment, the liquid composition comprises nimodipine and asolvent system from about 5% to about 20% (w/v) water and from about 80%to about 95% (w/v) polyethylene glycol.

In one embodiment, the liquid composition comprises nimodipine and asolvent system comprising water, polyethylene glycol, and ethanol. Theamount of ethanol in the solvent system can vary from about 0.5% toabout 5% (w/v), preferably from about 1% to less than about 5%, morepreferably from about 0.5% to about 1%, as it has been found that higheramounts of ethanol lead to reduced nimodipine solubility (Example 2).The amount of water in the solvent system can vary from about 1% toabout 35% (w/v), such as, for example, from about 1% to about 30%, fromabout 1% to about 25%, from about 1% to about 20%, from about 1% toabout 15%, from about 1% to about 10%, from about 1% to about 5%, fromabout 5% to about 35%, from about 5% to about 30%, from about 5% toabout 25%, from about 5% to about 20%, from about 5% to about 15%, fromabout 5% to about 10%, from about 10% to about 35%, from about 10% toabout 30%, from about 10% to about 25%, from about 10% to about 20%,from about 10% to about 15%, from about 15% to about 35%, from about 15%to about 30%, from about 15% to about 25%, from about 15% to about 20%,from about 20% to about 35%, from about 20% to about 30%, from about 20%to about 25%, from about 25% to about 35%, from about 25% to about 30%,or from about 30% to about 35%. The amount of polyethylene glycol in thesolvent system can vary from about 65% to about 97% (w/v), such as, forexample, from about 65% to about 95%, from about 65% to about 95%, fromabout 65% to about 90%, from about 65% to about 80%, from about 65% toabout 70%, from about 70% to about 97%, from about 70% to about 95%,from about 70% to about 90%, from about 70% to about 80%, from about 80%to about 97%, from about 80% to about 95%, from about 80% to about 90%,or from about 90% to about 97%, from about 90% to about 95%. In aparticular embodiment, the liquid composition comprises nimodipine and asolvent system consisting of water, polyethylene glycol, and ethanol.

In a particular embodiment, the liquid composition comprises nimodipineand a solvent system comprising from about 0.5% to about 5% (w/v)ethanol, from about 1% to about 35% (w/v) water, and from about 65% toabout 97% (w/v) polyethylene glycol. In another particular embodiment,the liquid composition comprises nimodipine and a solvent systemcomprising from about 0.5% to about 5% (w/v) ethanol, from about 1% toabout 5% (w/v) water, and from about 50% to about 97% (w/v) polyethyleneglycol. In still another particular embodiment, the liquid compositioncomprises nimodipine and a solvent system comprising from about 0.5% toabout 1% (w/v) ethanol, from about 1% to about 5% (w/v) water, and fromabout 50% to about 97% polyethylene glycol.

In one embodiment, the liquid composition comprises nimodipine and asolvent system comprising water, polyethylene glycol, ethanol, andglycerin. The amount of ethanol in the solvent system can vary fromabout 0.4% to about 1% (w/v). The amount of water in the solvent systemcan vary from about 1% to about 25% (w/v), such as, for example, fromabout 1% to about 20%, from about 1% to about 15%, from about 1% toabout 10%, from about 1% to about 5%, from about 5% to about 25%, fromabout 5% to about 20%, from about 5% to about 15%, from about 5% toabout 10%, from about 10% to 25%, from about 10% to about 20%, fromabout 10% to about 15%, from about 15% to about 25%, from about 15% toabout 20% or from about 20% to about 25%. The amount of polyethyleneglycol in the solvent system can vary from about 50% to about 97% (w/v),such as, for example, from about 50% to about 95%, from about 50% toabout 90%, from about 50% to about 80%, from about 50% to about 70%,from about 50% to about 60%, from about 60% to about 95%, from about 60%to about 95%, from about 60% to about 90%, from about 60% to about 80%,from about 60% to about 70%, from about 70% to about 97%, from about 70%to about 95%, from about 70% to about 90%, from about 70% to about 80%,from about 80% to about 97%, from about 80% to about 95%, from about 80%to about 90%, or from about 90% to about 97%, from about 90% to about95%. The amount of glycerin in the solvent system can vary from about 1%to about 50% (w/v), such as, for example, from about 1% to about 40%,from about 1% to about 30%, from about 1% to about 20%, from about 1% toabout 10%, from about 10% to about 50%, from about 10% to about 40%,from about 10% to about 30%, from about 10% to about 20%, from about 20%to about 50%, from about 20% to about 40%, from about 20% to about 30%,from about 30% to about 50%, from about 30% to about 40%, or from about40% to about 50%. In a particular embodiment, the liquid compositioncomprises nimodipine and a solvent system consisting of water,polyethylene glycol, ethanol, and glycerin.

In a particular embodiment, the liquid composition comprises nimodipineand a solvent system comprising 0.4% to about 1% (w/v) ethanol, fromabout 1% to about 25% (w/v) water, from about 50% to about 97% (w/v)polyethylene glycol, and from about 1% to about 50% (w/v) glycerin. Inanother embodiment, the liquid composition comprises nimodipine and asolvent system comprising 0.4% to about 1% (w/v) ethanol, from about 1%to about 5% (w/v) water, from about 50% to about 97% (w/v) polyethyleneglycol, and from about 1% to about 50% (w/v) glycerin. In still anotherparticular embodiment, the liquid composition comprises nimodipine and asolvent system comprising about 0.4% to about 1% (w/v) ethanol, fromabout 1% to about 10% (w/v) water, from about 55% to about 75% (w/v)polyethylene glycol and from about 20% to about 40% (w/v) glycerin.

In one embodiment, the liquid composition consists essentially ofnimodipine and one or more solvents listed above.

In other embodiments, the liquid composition comprises one or moreadditional excipients, such as, for example, buffering agents and/orpreservatives.

Exemplary buffering agents include, but are not limited to, benzoicacid, phosphoric acid, tartaric acids, lactic acid, succinic acid,citric acid, acetic acid, ascorbic acid, aspartic acid, hydrochloricacid, sulfuric acid, glutamic acid, and salts thereof. In a particularembodiment, the buffering agent comprises sodium benzoate and benzoicacid.

In one embodiment, the preservative comprises from about 0.01% to about0.1% (w/v) of the liquid composition.

The preservative can be from the paraben family. Exemplary parabenpreservatives include, but are not limited to, methylparaben,propylparaben, ethylparaben, butylparaben, isobutylparaben,isopropylparaben, benzylparaben, sodium salts of the referencedparabens, or mixtures of thereof.

The preservative can be a sorbate (salt of sorbic acid and/or sorbicacid), benzoate (salt of benzoic acid and/or benzoic acid), sulfurdioxide, sulfite, nitrite, nitrate, lactic acid, propionic acid,propionate, ascorbic acid, ascorbate, butylated hydroxytoluene orcombinations thereof. In one embodiment, the preservative comprisessodium benzoate and benzoic acid.

In one embodiment, the preservative comprises from about 0.01% to about1% (w/v) of the liquid composition.

In still another embodiment, the liquid composition comprises an agentthat functions as both a buffer and a preservative, e.g. sodium benzoateand benzoic acid.

The liquid composition comprises nimodipine in an effective amount perdosage unit. In one embodiment, the liquid composition comprises fromabout 10 mg to about 100 mg nimodipine per dosage unit, such as, forexample, at least about 30 mg, at least about 40 mg, at least about 50mg, at least about 60 mg or at least about 70 mg. In a particularembodiment, the liquid composition comprises about 60 mg or morenimodipine per dosage unit. In a more particular embodiment, the liquidcomposition comprises about 60 mg nimodipine per dosage unit.

The amount of solvent in the dosage unit can vary. In one embodiment,the liquid composition comprises from about 1 mL to about 20 mL solventper dosage unit, such as, for example, from about 5 mL to about 20 mL,from about 5 mL to about 15 mL, from about 5 mL to about 10 mL, fromabout 10 mL to about 20 mL, from about 10 mL to about 15 mL or fromabout 15 mL to about 20 mL. In a particular embodiment, the liquidcomposition comprises about 5 mL of solvent per dosage unit. In anotherparticular embodiment, the liquid composition comprises about 10 mL ofsolvent per dosage unit. In still another particular embodiment, theliquid composition comprises about 20 mL of solvent per dosage unit.

Accordingly, the concentration of nimodipine in the liquid compositionof the present invention is greater than about 3 mg/mL, such as, forexample, at least about 4 mg/mL, at least about 5 mg/mL, at least about6 mg/mL, at least about 7 mg/mL, at least about 8 mg/mL, at least about9 mg/mL, at least about 10 mg/mL, at least about 11 mg/mL, at leastabout 12 mg/mL, at least about 13 mg/mL, at least about 14 mg/mL, atleast about 15 mg/mL, at least about 16 mg/mL, at least about 17 mg/mL,at least about 18 mg/mL, at least about 19 mg/mL or at least about 20mg/mL.

In another embodiment, the concentration of nimodipine in the liquidcomposition is between any of the concentrations recited above, such as,for example, from about 5 mg/mL to about 20 mg/mL, from about 5 mg/mL toabout 15 mg/mL, from about 5 mg/mL to about 10 mg/mL, about 10 mg/mL toabout 20 mg/mL, from about 10 mg/mL to about 15 mg/mL and from about 15mg/mL to about 20 mg/mL.

In a particular embodiment, the concentration of nimodipine in theliquid composition of the present invention is about 3 mg/mL to about 10mg/mL, about 3 mg/mL to about 9 mg/mL, about 3 mg/mL to about 8 mg/mL,about 3 mg/mL to about 7 mg/mL, about 3 mg/mL to about 6 mg/mL, about 3mg/mL to about 5 mg/mL, or about 3 mg/mL to about 4 mg/mL.

In another particular embodiment, the concentration of nimodipine in theliquid composition of the present invention is about 4 mg/mL to about 10mg/mL, about 4 mg/mL to about 9 mg/mL, about 4 mg/mL to about 8 mg/mL,about 4 mg/mL to about 7 mg/mL, about 4 mg/mL to about 6 mg/mL or about4 mg/mL to about 5 mg/mL.

In yet another particular embodiment, the concentration of nimodipine inthe liquid composition of the present invention is about 5 mg/mL toabout 10 mg/mL, about 5 mg/mL to about 9 mg/mL, about 5 mg/mL to about 8mg/mL, about 5 mg/mL to about 7 mg/mL, or about 5 mg/mL to about 6mg/mL.

In another particular embodiment, the concentration of nimodipine in theliquid composition of the present invention is about 6 mg/mL to about 10mg/mL, about 6 mg/mL to about 9 mg/mL, about 6 mg/mL to about 8 mg/mL orabout 6 mg/mL to about 7 mg/mL.

In one embodiment, the concentration of nimodipine in the liquidcomposition of the present invention is about 7 mg/mL to about 10 mg/mL,about 7 mg/mL to about 9 mg/mL or about 7 mg/mL to about 8 mg/mL.

In another embodiment, the concentration of nimodipine in the liquidcomposition of the present invention is about 8 mg/mL to about 10 mg/mLor about 8 mg/mL to about 9 mg/mL

In still another embodiment, the concentration of nimodipine in theliquid composition is any of the concentrations recited above, such as,for example, about 4 mg/mL, about 5 mg/mL, about 6 mg/mL, about 7 mg/mL,about 8 mg/mL, about 9 mg/mL, about 10 mg/mL, about 11 mg/mL, about 12mg/mL, about 13 mg/mL, about 14 mg/mL, about 15 mg/mL, about 16 mg/mL,about 17 mg/mL, about 18 mg/mL, about 19 mg/mL or about 20 mg/mL.

In preferred embodiments, a dosage unit of the liquid compositioncomprises 60 mg nimodipine in about 5 mL solvents to about 10 mL ofsolvents, such as, for example, about 5 mL of solvent (12 mg/mL) orabout 10 mL (6 mg/mL).

The density of the liquid composition may vary. In one embodiment, thedensity is between about 0.8 and about 1.8, such as, for example,between about 0.8 and about 1.0, about 1.0 and about 1.2, about 1.2 andabout 1.4, about 1.4 and about 1.6, about 1.6 and about 1.8. In anotherembodiment, the density is about 0.8, about 0.9, about 1.0, about 1.1,about 1.2, 1.3, about 1.4, about 1.5, about 1.6, about 1.7 or about 1.0.

In a particular embodiment, the density is between 1.10 and about 1.26,more particularly, about 1.12 and about 1.24, about 1.14 and about 1.22,about 1.16 and about 1.20, and even more particularly, about 1.10, about1.11, about 1.12, about 1.13, about 1.14, about 1.15, about 1.16, about1.17, about 1.18, about 1.19, about 1.20, about 1.21, about 1.22, about1.23, about 1.24, about 1.25 or about 1.26.

The liquid compositions of the present invention do not exhibitsubstantial nimodipine degradation when exposed to certain studyconditions. Stability may be measured by any suitable method, e.g., byhigh-performance liquid chromatography (HPLC). In a particularembodiment, the liquid compositions of the present invention do notexhibit substantial nimodipine degradation under hydrolytic conditions,oxidative conditions, photolytic conditions, thermal conditions orcombinations thereof. In another particular embodiment, the liquidcompositions of the present invention do not exhibit substantialnimodipine degradation under forced stability conditions, acceleratedstability conditions, real-time stability conditions or a combinationthereof.

In some embodiments, the liquid compositions disclosed herein do notexhibit substantial degradation under accelerated conditions (e.g. 40°C. and 75% relative humidity) for at least 3 months, at least 6 months,at least 8 months, at least 10 months, at least 12 months, or at least24 months. Methods of measuring nimodipine degradation are known to aperson of skill in the art, e.g., monitoring the amount of nimodipine inthe liquid composition by HPLC over a period of time. An exemplarymethod is provided in Example 1 infra.

In one embodiment, the liquid composition exhibits about 5% or lessnimodipine degradation over at least a three-month period when exposedto 40° C. and 75% relative humidity, such as, for example, about 4.5% orless, 4.0% or less, about 3.5% or less, about 3.0% or less, about 2.5%or less, about 2.0% or less, about 1.5% or less or about 1.0% or less.

In a particular embodiment, the liquid composition exhibits about 1.0%or less nimodipine degradation over at least a three-month period whenexposed to 40° C. and 75% relative humidity, such as, for example, about0.90% or less, about 0.80% or less, about 0.70% or less, about 0.60% orless, about 0.50% or less, about 0.40% or less, about 0.30% or less,about 0.20% or less or about 0.10% or less.

In one embodiment, the liquid composition comprises a relatively smalleramount of nimodipine degradation compared with NYMALIZE® over at least athree month period when exposed to 40° C. and 75% relative humidity,i.e., less than about 5% degradation, from about 3% to about 4%degradation, from about 1% to about 2% degradation, from 0.01% to about1% degradation, from about 0.01% to about 0.9% degradation, from about0.01% to about 0.8% degradation, from about 0.01% to about 0.7%degradation, from about 0.01% to about 0.6% degradation, from about0.01% to about 0.5% degradation, from about 0.01% to about 0.4%degradation, from about 0.01% to about 0.3% degradation, from about0.01% to about 0.2% degradation, from about 0.01% to about 0.1%degradation and from about 0.01% to about 0.05% degradation.

In one embodiment, the liquid composition exhibits between about 0.50%and about 4.0%, about 0.50% and about 0.35%, about 0.5% and about 0.30%,about 0.50% and about 0.20%, about 0.50% and about 0.10%; about 0.10%and about 4.0%, about 1.0% and about 3.5%, about 1.0% and about 3.0%,about 1.0% and about 2.5%, about 1.0% and about 2.0%, about 1.5% andabout 4.0%, about 1.5% and about 3.5%, about 1.5% and about 3.0%, about1.5% and about 2.5%, about 1.5% and about 2.0%, about 2.0% and about 2.5nimodipine degradation over at least a three month period when exposedto 40° C. and 75% relative humidity

In a particular embodiment, the liquid composition exhibits about 95% orless, about 90% or less, about 85% or less, about 80% or less, about 76%or less, about 70% or less, about 65% or less, 60% or less, about 55% orless, about 50% or less, about 45% or less, about 40% or less, about 35%or less, about 30% or less, about 25% or less, about 20% or less, about15% or less, about 10% or less nimodipine degradation than NYMALIZE®over at least a three month period when exposed to 40° C. and 75%relative humidity.

In another particular embodiment, the liquid composition exhibits about1.0% to about 90%, about 1.0% and about 80%, about 1.0% and about 70%,about 1.0% and about 60%, about 1.0% and about 50%, about 1.0% to about40%, about 1.0% to about 30%, about 1.0% to about 20%, about 1.0% toabout 10% or less nimodipine degradation than NYMALIZE® over at least athree-month period when exposed to 40° C. and 75% relative humidity.

In another particular embodiment, the liquid composition exhibits about10% to about 90%, about 10% and about 80%, about 10% and about 70%,about 10% and about 60%, about 10% and about 50%, about 10% to about40%, about 10% to about 30%, or about 10% to about 20% less nimodipinedegradation than NYMALIZE® over at least a three-month period whenexposed to 40° C. and 75% relative humidity.

In another particular embodiment, the liquid composition exhibits about20% to about 90%, about 20% and about 80%, about 20% and about 70%,about 20% and about 60%, about 20% and about 50%, about 20% to about40%, or about 20% to about 30% less nimodipine degradation thanNYMALIZE® over at least a three-month period when exposed to 40° C. and75% relative humidity.

In yet another particular embodiment, the liquid composition exhibitsabout 40 to about 70% or about 50 to about 60% less nimodipinedegradation than NYMALIZE® over at least a three-month period whenexposed to 40° C. and 75% relative humidity.

One particular nimodipine degradation product that can be minimizedusing the liquid compositions of the present invention is nimodipinerelated compound A. In certain embodiments, the liquid compositioncomprises from 0.01% to about 1.5% nimodipine related compound A over atleast a three-month period when exposed to 40° C. and 75% relativehumidity, such as, for example, from about 0.01% to about 0.1% and fromabout 0.01% to about 0.05%.

In a particular embodiment, the liquid composition comprises about 1.9%or less nimodipine related compound A over at least a three month periodwhen exposed to 40° C. and 75% relative humidity, or more particularly,about 1.8% or less, about 1.7% or less, about 1.6% or less, about 1.5%or less, about 1.4% or less, about 1.3 or less, or about 1.2% or less.In a particular embodiment, the liquid composition comprises about 1.9%or less nimodipine related compound A over at least six-month periodwhen exposed to 40° C. and 75% relative humidity

In a particular embodiment, the liquid composition comprises about 1.2%or less nimodipine related compound A over at least a three month periodwhen exposed to 40° C. and 75% relative humidity, or more particularly,about 1.0% or less, about 0.90% or less, about 0.80% or less, about0.70% or less, about 0.60% or less, about 0.50% or less, about 0.40% orless, about 0.30% or less, about 0.20% or less, about 0.10% or lessabout 0.08% or less, about 0.06% or less, about 0.04% or less, about0.02% or less, or about 0.01% or less nimodipine related compound A.

In one embodiment, the liquid composition comprises from 0.01% to about1.2% nimodipine related compound A over at least a three month periodwhen exposed to 40° C. and 75% relative humidity, and more particularly,about 0.01% to about 1.0%, about 0.01% to about 0.20%, about 0.01% toabout 0.40%, about 0.01 to about 0.60%, about 0.01% to about 0.80%,about 0.01% to about 1.0%, about 0.01% to about 1.2% nimodipine relatedcompound A.

In one embodiment, the liquid composition comprises from 0.1% to about1.2% nimodipine related compound A over at least a three-month periodwhen exposed to 40° C. and 75% relative humidity, and more particularly,about 0.1% to about 1.0%, about 0.1% to about 0.20%, about 0.1% to about0.40%, about 0.1 to about 0.60%, about 0.1% to about 0.80%, about 0.1%to about 1.0%, about 0.1% to about 1.2% nimodipine related compound A.

In a particular embodiment, the liquid composition containssubstantially no nimodipine related compound A over at least athree-month period when exposed to 40° C. and 75% relative humidity

In one embodiment, the liquid composition contains about 100% or less,95% or less, about 90% or less, about 85% or less, about 80% or less,about 75% or less, about 70% or less, about 65% or less, about 60% orless, about 55% or less, about 50% or less, about 45% or less, about 40%or less, about 35% or less, about 30% or less, about 25% or less, about20% or less, about 15% or less, or about 10% or less nimodipine relatedcompound A than NYMALIZE® over at least a three month period whenexposed to 40° C. and 75% relative humidity.

In a particular embodiment, the liquid composition contains betweenabout 1.0% and about 90% less, about 1.0% and about 80% less, about 1.0%and 70%, about 1.0% and about 60%, about 1.0% and about 50%, about 1.0%and about 30%, about 1.0% and about 20%, about 1.0% and about 10%, about1.0% and about 5.0% less nimodipine related compound A than NYMALIZE®over at least a three-month period when exposed to 40° C. and 75%relative humidity,

In a particular embodiment, the liquid composition contains betweenabout 10% and about 90% less, about 10% and about 80% less, about 10%and 70%, about 10% and about 60%, about 10% and about 50%, about 10% andabout 30%, about 10% and about 20%, about 20% and about 90%, about 20%and about 80%, about 20% and about 70%, about 20% and about 60%, about20% and about 50%, about 20% and about 40%, about 20% and about 30%,about 30% and about 90%, about 30% and about 80%, about 30% and about70%, about 30% and about 60%, about 30% and about 50%, or about 30% andabout 40% less nimodipine related compound A than NYMALIZE® over atleast a three month period when exposed to 40° C. and 75% relativehumidity.

In one embodiment, the liquid composition of the present inventioncomprises less than about 3.0% total impurities over at least athree-month period when exposed to 40° C. and 75% relative humidity suchas, for example, about 2.9% or less, about 2.8% or less, about 2.6% orless, about 2.4% or less, about 2.2% or less, or about 2.0% or lesstotal impurities.

In one embodiment, the liquid composition of the present inventioncomprises less than about 2.0% total impurities over at least athree-month period when exposed to 40° C. and 75% relative humidity suchas, for example, about 1.9% or less, about 1.8% or less, about 1.6% orless, about 1.4% or less, about 1.2% or less, about 1.0% or less, about0.8% or less or about 0.6%, about 0.4% or less or about 0.2% or lesstotal impurities.

In a particular embodiment, the liquid composition of the presentinvention comprises between about 0.1% and about 2.0% total impuritiesover at least a three month period when exposed to 40° C. and 75%relative humidity, or more particularly, about 0.1% and about 1.8%,about 0.1% and about 1.6% total impurities, about 0.1% and about 1.4%,about 0.1% and about 1.2%, about 0.1% and 1.0%, about 0.1% and about0.8%, about 0.1% and about 0.6%, about 0.1% and about 0.4%, or about0.1% and about 0.2% total impurities.

In one embodiment, the liquid composition contains about 100% or less,95% or less, about 90% or less, about 85% or less, about 80% or less,about 75% or less, about 70% or less, about 65% or less, about 60% orless, about 55% or less, about 50% or less, about 45% or less, about 40%or less, about 35% or less, about 30% or less, about 25% or less, about20% or less, about 15% or less, or about 10% or less total impuritiesthan NYMALIZE® over at least a three month period when exposed to 40° C.and 75% relative humidity.

In one embodiment, the liquid composition comprises about 1.0% and about90% less, about 1.0% and about 80% less, about 1.0% and 70%, about 1.0%and about 60%, about 1.0% and about 50%, about 1.0% and about 30%, about1.0% and about 20%, about 1.0% and about 10%, or about 1.0% and about5.0% less total impurities than NYMALIZE® over at least a three-monthperiod when exposed to 40° C. and 75% relative humidity.

In one embodiment, the liquid composition comprises about 10% and about90% less, about 10% and about 80% less, about 10% and 70%, about 10% andabout 60%, about 10% and about 50%, about 10% and about 30%, about 10%and about 20% less total impurities than NYMALIZE® over at least athree-month period when exposed to 40° C. and 75% relative humidity.

In one embodiment, the liquid composition comprises about 20% and about90% less, about 20% and about 80% less, about 20% and 70%, about 20% andabout 60%, about 20% and about 50%, or bout 20% and about 30% less totalimpurities than NYMALIZE® over at least a three-month period whenexposed to 40° C. and 75% relative humidity.

In one embodiment, the liquid composition comprises about between about40 and about 70% or about 50 and about 60% less total impurities thanNYMALIZE® over at least a three-month period when exposed to 40° C. and75% relative humidity.

In one embodiment, the liquid compositions of the present inventioncomprise substantially no impurities over at least a three month periodwhen exposed to 40° C. and 75% relative humidity.

In some embodiments, the liquid compositions disclosed herein do notexhibit substantial degradation under ambient conditions (e.g. 25° C.and 60% relative humidity) for at least 3 months, at least 6 months, atleast 8 months, at least 10 months, at least 12 months, or at least 24months. In a particular embodiment, the liquid compositions disclosedherein do not exhibit substantial degradation under ambient conditions(e.g. 25° C. and 60% relative humidity) about 24 months or greater, suchas, e.g., 26 months, 28 months, 30 months or more.

In a particular embodiment, the liquid compositions disclosed herein donot exhibit 10% or more nimodipine degradation over at least a threemonth period when exposed to 25° C. and 60% relative humidity and moreparticularly, about 9% or more, about 8% or more, about 7% or more,about 6% or more, about 5% or more, about 4% or more, about 3% or more,about 2% or more, about 1% or more. In a particular embodiment, theliquid compositions disclosed herein do not exhibit about 1.0% or morenimodipine degradation over at least a three-month period when exposedto 25° C. and 60% relative humidity and more particularly, about 0.9% ormore, about 0.8% or more, about 0.7% or more, about 0.6% or more about0.5% or more, about 0.4% or more, about 0.3% or more, about 0.2% ormore, about 0.1% or more or about 0.01% or more.

One particular nimodipine degradation product that can be minimizedusing the liquid compositions of the present invention is nimodipinerelated compound A.

In one embodiment, the liquid composition comprises 1.2% or lessnimodipine related compound A over at least a three-month period whenexposed to 25° C. and 60% relative humidity, or more particularly, about1.2% or less, about 1.1% or less, about 1.0% or less, about 0.9% or lessor about 0.8% or less nimodipine related compound A.

In one embodiment, the liquid composition comprises 0.6% or lessnimodipine related compound A over at least a three-month period whenexposed to 25° C. and 60% relative humidity.

In one embodiment, the liquid composition comprises 0.5% or lessnimodipine related compound A over at least a three-month period whenexposed to 25° C. and 60% relative humidity, and more particularly, 0.4%or less, 0.35% or less, 0.30% or less, 0.25% or less, 0.20% or less,0.15% or less, 0.10% or less or 0.05% or less nimodipine relatedcompound A.

In certain embodiments, the liquid composition comprises from 0.01% toabout 0.35% nimodipine related compound A over at least a three monthperiod when exposed to 25° C. and 60% relative humidity, such as, forexample, from about 0.01% to about 0.30%, about 0.01% to about 0.25%,about 0.01% to about 0.20%, about 0.01% to about 0.15%, about 0.01% toabout 0.10%; about 0.1% to about 0.35%, about 0.10% to about 0.30%,about 0.10% to about 0.25%, about 0.10% to about 0.20% or about 0.10% toabout 0.15% nimodipine related compound A.

In a particular embodiment, the liquid composition contains about 95% orless, about 90% or less, about 85% or less, about 80% or less, about 75%or less, about 70% or less, about 65% or less, about 60% or less, about55% or less, about 50% or less, about 45% or less, about 40% or less,about 35% or less, about 30% or less, about 25% or less, about 20% orless, about 15% or less or about 10% or less nimodipine related compoundA than NYMALIZE® over at least a three month period when exposed to 25°C. and 60% relative humidity,

In another particular embodiment, the liquid composition containsbetween about 50% and about 100% less, between about 50% and about 95%less, between about 50% and about 85% less, between about 50% and about80% less, between about 50% and about 75% or between about 50% and about70% or less nimodipine related compound A than NYMALIZE® over at least athree-month period when exposed to 25° C. and 60% relative humidity.

In one embodiment, the liquid composition contains substantially nonimodipine related compound A over at least a three-month period whenexposed to 25° C. and 60% relative humidity.

In one embodiment, the total impurities in liquid compositions of thepresent invention comprises less than about 1.8% over at least athree-month period when exposed to 25° C. and 60% relative humidity,such as, for example, about 1.6% or less, about 1.4% or less, about1.2%, about 1.0% or less, about 0.8% or less, about 0.6% or less, about0.4% or less, about 0.2% or less, about 0.1% or less or 0.0% or lesstotal impurities.

In one embodiment, the total impurities in liquid compositions of thepresent invention comprises less than about 0.7% over at least athree-month period when exposed to 25° C. and 60% relative humidity,such as, for example, about 0.5% or less or about 0.3% or less, and moreparticularly, less than about 0.6%, less than about 0.5%, less thanabout 0.4%, less than about 0.3%, less than about 0.2%, less than about0.1%, less than about 0.05% or less than about 0.01% total impurities.

In one embodiment, the liquid compositions of the present inventioncomprise about 100% or less total impurities than NYMALIZE® over atleast a three month period when exposed to 25° C. and 60% relativehumidity,

In one embodiment, the liquid composition of the present inventioncomprises about 95% or less total impurities than NYMALIZE® over atleast a three month period when exposed to 25° C. and 60% relativehumidity, such as, e.g., about 90% or less, about 85% or less, about 80%or less, about 75% or less, about 70% or less, about 65% or less, about60% or less, about 55% or less, about 50% or less, about 45% or less,about 40% or less, about 35% or less, about 30% or less, about 25% orless, about 20% or less, about 15% or less, about 10% or less about 5%or less total impurities.

In one embodiment, the liquid composition of the present inventioncomprises substantially no total impurities over at least a three-monthperiod when exposed to 25° C. and 60% relative humidity.

In one embodiment, the liquid composition is packaged as a single dosageunit. In an alternate embodiment, the liquid composition is packaged ina container containing multiple dosage units, e.g., a bottle. In stillanother embodiment, the liquid composition is packaged into a pre-filledsyringe. The liquid composition can be dispensed, for example, byloading into an automated medication dispensing system, by extractionwith an oral dosing device, such as a cup or syringe, or by pouring thecomposition directly into a device (e.g., a syringe or machine) foradministration to a patient. Other means for providing, preparing,storing, transporting, and dispensing pharmaceutical compositions areknown to those skilled in the art.

In one embodiment, the shelf life of the liquid composition is increasedrelative to compared with NYMALIZE®. The shelf-life of a drug isgenerally defined as the length of time a drug can stay on the shelfwithout degrading to unacceptable levels of chemical potency orpharmaceutical utility. Shelf-life may be determined by any suitablemethod.

In a particular embodiment, the shelf life of the liquid composition isincreased by about 5%, about 10%, about 15%, about 20%, about 25%, about30%, about 35%, about 40%, about 45%, about 50% or more.

In another particular embodiment, the shelf life of the liquidcomposition is increased by about one week, about two weeks, about threeweeks, about four weeks, up to one month, up to 2 months, up to 3months, up to 4 months, up to 5 months, up to 6 months or more than 6months.

In one embodiment, the shelf life of the liquid when it is contained ina suitable container exhibits a shelf life of at least 6 months, morepreferably at least 12 months, still more preferably at least 15 months,yet more preferably at least 18 months, most preferably at least 21months and in particular at least 24 months. In one embodiment, theshelf-life is greater than 24 months, e.g., 26 months, 28 months, 30months or more.

In one embodiment, the shelf life of the liquid composition when it iscontained in a suitable container container exhibits a shelf life underambient conditions of at least 6 months, more preferably at least 12months, still more preferably at least 15 months, yet more preferably atleast 18 months, most preferably at least 21 months and in particular atleast 24 months. In one embodiment, the shelf-life is greater than 24months, e.g., 26 months, 28 months, 30 months or more.

III. METHODS

The present invention provides a method of treating a disorder, orsymptoms associated with a disorder, for which nimodipine provides atherapeutic effect. Nimodipine acts as a vasodilator and is consideredto be a calcium channel blocker and was approved by the FDA to improveneurological outcome after subarachnoid hemorrhage (SAH) from rupturedblood vessels in the brain.

Accordingly, the present invention provides a method of improvingneurological outcome by reducing the incidence and severity of ischemicdeficits in patients with subarachnoid hemorrhage from rupturedintracranial berry aneurysms comprising administering to a patient inneed thereof an effective amount of a liquid composition comprisingnimodipine described supra.

The liquid composition is preferably administered enterally. Suitableenteral administration routes include, but are not limited to, oral, vianasogastric tube or via gastric tube. In a particular embodiment, theliquid composition is administered to the patient via nasogastric tube.

A dosage unit of the liquid composition is first administered after thesubarachnoid hemorrhage, such as, for example, within about 100 hours ofthe subarachnoid hemorrhage, within about 90 hours of the subarachnoidhemorrhage, within about 80 hours of the subarachnoid hemorrhage, withinabout 70 hours of the subarachnoid hemorrhage, within about 60 hours ofthe subarachnoid hemorrhage, within about 50 hours of the subarachnoidhemorrhage, within about 40 hours of the subarachnoid hemorrhage, withinabout 30 hours of the subarachnoid hemorrhage, within about 20 hours ofthe subarachnoid hemorrhage, within about 10 hours of the subarachnoidhemorrhage or within about 5 hours of the subarachnoid hemorrhage. In aparticular embodiment, a dosage unit of the liquid composition isadministered within about 96 hours of the subarachnoid hemorrhage.

A dosage unit of the liquid composition can be administered to thepatient once a day or multiple times a day, such as, for example, twiceor more per day, three times or more per day, four times or more perday, five times or more per day or six times or more per day.

A dosage unit of the liquid composition can be administered in variousintervals, such as, for example, every two hours, every four hours,every six hours, every eight hours, every 12 hours or every 24 hours. Ina particular embodiment, a dosage unit of the liquid composition isadministered to the patient every four hours.

The duration of treatment can vary. In one embodiment, treatment iscontinued for at least 7 days, at least 14 days, at least 21 days or atleast 30 days. In a particular embodiment, the dosing regimen iscontinued for 21 days.

In exemplary embodiments, a dosage unit of the liquid composition isadministered every four hours for 21 days. The first dosage unit isadministered within 96 hours of the subarachnoid hemorrhage. The dosageunit preferably comprises 60 mg nimodipine.

The liquid composition can be dosed before or after feeding. In oneembodiment, a dosage unit is administered about 1 hour prior to a meal.In another embodiment, a dosage unit is administered about two hoursafter a meal.

The present invention also provides a method of treating otherconditions including, but not limited to, vasospastic angina,Prenzmetal's angina, stable angina, acute myocardial infarction,myocardial arrest, arrhythmia, systemic hypertension, pulmonaryhypertension, congestive heart failure, and hypertrophic cardiomyopathycomprising administering to a patient in need thereof an effectiveamount of a liquid composition comprising nimodipine described supra.

In a particular embodiment, the method of the present invention isassociated with decreased instances of diarrhea compared to NYMALIZE®,i.e., about 100%, about 90%, about 80%, about 70%, about 60%, about 50%,about 40%, about 30%, about 20%, about 10% decrease in instance measuredover the period of a day, week or month.

EXAMPLES Example 1: Stability Study

Two non-aqueous liquid compositions of the present invention werecompared to NYMALIZE® over the course of a 3-month accelerated stabilitystudy. The non-aqueous liquid compositions were prepared with thefollowing ingredients:

A. Formulation A (2017NIM009)

A 10 liter batch was prepared with the ingredients shown in Table 1,below. The pH of the batch was adjusted to within pH 6 to 7 with 6N HCland 6N NaOH after completion.

TABLE I Formula A (2017NIM009) Theoretical Actual Material % W/V Amount(g) Amount (g) Nimodipine 0.60 60.00 60.06 PEG 400 68.00 6,800.006,806.64 Ethanol 95% 0.395 39.50 39.51 Glycerin 47.505 4,750.50 4,757.62Total 116.5 11,650.00 11,663.83

B. Formulation B (2017nim010)

A 10 liter batch was prepared with the ingredients shown in Table II,below.

TABLE II Formula B (2017NIM010) Theoretical Actual Material % W/V Amount(g) Amount (g) Nimodipine 0.60 60.00 60.00 PEG 400 68.00 6,800.006,800.54 Ethanol 95% 0.395 39.50 39.52 Glycerin 47.505 4,745.25 4,750.09Benzoic Acid 0.0375 3.75 3.75 Sodium 0.015 1.50 1.50 Benzoate Total116.5 11,650.00 11,655.40

C. Formulation C (2017NIM013)

A 5 liter batch was prepared with the ingredients shown in Table III,below:

TABLE III Formulation C (2017NIM013) Theoretical Actual Material % W/VAmount (g) Amount (g) Nimodipine 0.60 30.00 30.00 PEG 400 68.00 3400.003410.00 Ethanol 95% 0.395 19.975 19.78 Glycerin 47.505 2375.25 2374.33Methylparaben 0.20 10.00 10.00 Total 116.7 5835.00 (5000 mL) 5844.11

Samples of all three compositions were stored at 40° C. and 75% relativehumidity (RH). The amount of nimodipine present in the same was measuredat one month, two month and three-month time points by HPLC. Formationof degradants (“related substances”) and nimodipine related compound A(NRCA) were also measured by HPLC at the same time points. The resultsof the study are shown in Table IV, below:

TABLE IV Amount of Nimodipine/Formation of Degradants Over Time forNYMALIZE ® and Formulations A, B and C stored at 40° C. and 75% RHFormu- Formu- Formu- Time lation lation lation Period/ A B C StorageNYMA- (2017- (2017- (2017- Test Condition LIZE ® nim009) nim010) nim013)Assay Initial 100.1 101.7 102.4 103.9 (% LC) 1 month 40/75 98.5 103.4102.9 101.1 2 month 40/75 97.5 100.2 100.5 100.1 3 month 40/75 96.0100.1 99.4 101.5 6 month 40/75 92.1 100.1 97.8 99.9 Total Initial ND ND0.1 ND Impurities 1 month 40/75 0.80 0.21 0.51 0.10 2 month 40/75 1.400.45 0.69 0.13 3 month 40/75 2.10 0.99 0.77 0.40 6 month 40/75 3.0 1.51.9 ND Com- Initial ND ND 0.1 ND pound A 1 month 40/75 0.8 0.2 0.5 0.1 2month 40/75 1.4 0.5 0.7 0.1 3 month 40/75 2.1 1.0 0.8 0.4 6 month 40/753.0 1.5 1.9 ND ND = not detected

Samples of all three compositions were stored at 25° C. and 60% relativehumidity (RH). The amount of nimodipine present in the same was measuredat one month, two month and three month time points by HPLC. Formationof degradants (“related substances”) and nimodipine related compound A(NRCA) were also measured by HPLC at the same time points. The resultsof the study are shown below:

TABLE V Amount of Nimodipine/Formation of Degradants Over Time forNYMALIZE ® and Formulations A, B and C stored at 25° C. and 60% RHFormu- Formu- Formu- Time lation lation lation Period/ A B C StorageNYMA- (2017- (2017- (2017- Test Condition LIZE ® nim009) nim010) nim013)Assay Initial 100.1 101.7 102.4 103.9 (% LC) 1 month 25/60 _— _— —_ —_ 2month 25/60 _— _— —_ 101.6 3 month 25/60 100.3 100.6 101.6 100.6 6 month25/60 99.7 101.3 101.7 Total Initial 0.0 ND 0.1 ND Impurities 1 month25/60 _— _— _— ND 2 month 25/60 _— —_ _— ND 3 month 25/60 0.5 ND ND ND 6month 25/60 0.7 0.3 0.2 Com- Initial ND ND ND ND pound A 1 month 25/60_— _— —_ _— 2 month 25/60 _— _— —_ ND 3 month 25/60 0.4 ND ND ND 6 month25/60 0.6 0.1 0.1 ND Blank = ND

HPLC methodology for detection of nimodipine and for detection ofnimodipine related substances is as follows.

Detection of Nimodipine

An Inertsil ODS-2 150×4.6 mm HPLC column, 5 μm (example part number5020-01124) or equivalent column is used with a C8 or C18 pre-column(example part number Phenomenex AJO-4287 or equivalent). Reagents andsolutions include deionized water (CAS #7732-18-5), HPLC grade methanol(CAS #67-56-1), tetrahydrofuran (THF, CAS #109-99-9) and nimodipinereference standard (CAS #66085-59-4). A 1000 mL mobile phase solutionconsists of 600 mL water, 200 mL methanol and 200 mL tetrahydrofuran.Degas for 10 minutes.

Chromatographic Conditions

Column: Inertsil ODS-2 150×4.6 mm HPLC column, 5 example part number5020-01124 (GL Sciences) or equivalentGuard Column: C8 or C18 (example Phenomenex, Cat. No. AJO-4287) orequivalent

Temperature: 40° C. (Column)

Flow Rate: 1.8 mL/minuteDetection: Photodiode Array (PDA) detector

Injection Volume: 10 μL

Run Time: Approximately 45 minutes for Standard injections andapproximately 85 minutes for Sample injections.

Pump: Isocratic

Elution Time: If methylparaben is present in the formulation, theretention time (RT) is approximately 3 min. The retention time ofNimodipine Related Compound A is approximately 15-19 minutes. Theretention time of nimodipine is approximately 21-26 minutes.

Use a suitable HPLC system that provides comparable resolution,reproducibility, and sensitivity. Due to differences in columns andinstrumentation, it may be necessary to adjust the mobile phasecomposition and/or instrument parameters to achieve system suitabilityrequirements. Chromatographic parameters are not adversely affected bysmall HPLC parameter changes that could potentially be encountered inthe average laboratory environment or small variations in theperformance associated with HPLC equipment from different vendors.

The mobile phase contains a high concentration of tetrahydrofuran, whichcan lower the burst strength of some plastic materials. It isrecommended that the HPLC lines to and post column are composed ofstainless steel or other resistant materials.

To prepare the working standard solution, accurately weigh approximately60 mg of Nimodipine Reference Standard into a 50 mL actinic volumetricflask. Add 10 mL THF and sonicate 10 minutes to dissolve. Bring tovolume with mobile phase: Mix well.

Accurately weigh approximately 20 mL of sample solution into a lowactinic 50 mL volumetric flask. Add 10 mL of THF and shakemechanistically (for example, wrist-action shaker) for 5 minutes. Diluteto volume with mobile phase. Store at 4° C. (2-8° C.). Concentration isapproximately 1.2 mg/mL nimodipine.

Due to differences in columns and instrumentation, it may be necessaryto adjust the mobile phase composition and/or instrument parameters toachieve system suitability requirements. Chromatographic parameters arenot adversely affected by small HPLC parameter changes that couldpotentially be encountered in the average laboratory environment orsmall variations in the performance associated with HPLC equipment fromdifferent vendors. Please note that the nimodipine HPLC run needssufficient time to equilibrate. It is recommended that multiple workingstandard injections be performed for equilibration prior to analysis.Inject the Nimodipine Working Standard Solution. Inject a blank solutionof mobile phase to prevent possible carry-over. Inject the NimodipineSample Preparation. The absorption spectrum of the preparation of thetest specimen containing nimodipine exhibits maxima only at the samewavelengths as that of a similar preparation of the correspondingNimodipine Reference Standard. As the solvents included as part of thesample preparation can contribute to noise at the lower wavelengths, itis recommended that the spectrum comparison be performed between 220-400nm.

Detection of Nimodipine Related Substances

An Inertsil ODS-2 150×4.6 mm HPLC column, 5 μm (example part number5020-01124) or equivalent column is used with a C8 or C18 pre-column(example part number Phenomenex AJO-4287 or equivalent). Reagents andsolutions include deionized water (CAS #7732-18-5), HPLC grade methanol(CAS #67-56-1), tetrahydrofuran (THF, CAS #109-99-9), 3% hydrogenperoxide and nimodipine reference standard (CAS #66085-59-4). A 1000 mLmobile phase solution will consist of 600 mL water, 200 mL methanol and200 mL tetrahydrofuran. Degas for 10 minutes.

Chromatographic Conditions

Column: Inertsil ODS-2 150×4.6 mm HPLC column, 5 μm, example part number5020-01124 (GL Sciences) or equivalentGuard Column: C8 or C18 (example Phenomenex, Cat. No. AJO-4287) orequivalent

Temperature: 40° C. (Column)

Flow Rate: 1.8 mL/minuteDetection: UV absorbance at 271 nm.

Injection Volume: 10 μL

Run Time: Approximately 45 minutes for Standard injections andapproximately 85 minutes for Sample injections.

Pump: Isocratic

Elution Time: If methylparaben is present in the formulation, theretention time (RT) is approximately 3 min. The retention time ofNimodipine Related Compound A is approximately 15-19 minutes. Theretention time of nimodipine is approximately 21-26 minutes.

Use a suitable HPLC system that provides comparable resolution,reproducibility, and sensitivity. Due to differences in columns andinstrumentation, it may be necessary to adjust the mobile phasecomposition and/or instrument parameters to achieve system suitabilityrequirements. Chromatographic parameters are not adversely affected bysmall HPLC parameter changes that could potentially be encountered inthe average laboratory environment or small variations in theperformance associated with HPLC equipment from different vendors.

Please note that the mobile phase contains a high concentration oftetrahydrofuran, which can lower the burst strength of some plasticmaterials. It is recommended that the HPLC lines to and post column arecomposed of stainless steel or other resistant materials.

To prepare the standard solution, accurately weigh approximately 10 mg(+/−1 mg) of nimodipine Related Compound A Reference Standard into a 50mL actinic volumetric flask. Add 5 mL THF and sonicate 10 minutes todissolve. Bring to volume with mobile phase. Dilute to volume withmobile phase. Mix well. Store at 4° C. (Concentration is approximately0.2 mg/mL Related A). Transfer 3.0 mL of the above stock solution into a100 mL volumetric flask. Dilute to volume with mobile phase(Concentration is approximately 0.006 mg/ml Related A, or 0.5% of theanalytical sample concentration of Nimodipine Related Compound A).Prepare the above Nimodipine Related Compound A Reference Standard induplicate. The first preparation will be considered the NimodipineRelated Compound A Working Standard Solution, and the second preparationwill be considered the Nimodipine Related Compound A Check StandardSolution.

To prepare the resolution standard solution, accurately weighapproximately 60 mg of Nimodipine Reference Standard into a 50 mLactinic volumetric flask. Add 10 mL THF and sonicate 10 minutes todissolve. Bring to volume with mobile phase: Mix well. Pipette 5.0 mL ofthe above solution into a glass tube or other appropriate heat-resistantcontainer. Add 0.5 mL of the 3% hydrogen peroxide and heat at 90° C. inthe oven for 1 hour. Allow to cool to room temperature. Transferquantitatively into a low actinic 10 mL volumetric flask. Dilute tovolume with mobile phase. Mix well. Store at 4° C. Discard when analysesare complete.

After injecting the Resolution Standard, inject the mobile phase twelvetimes for greater than or equal to one minute each. For the Waters HPLCsystems, diluent may be injected eleven times for 4 minutes each, andonce for 10 minutes prior to injecting standards. The extended run time(extended from a run time of one minute per mobile phase injection) isto allow for equilibration of the baseline after elution of the solventfront and may be altered on a system to system basis. Please note thatthe intent of this preparation is not for quantitation, but to confirmresolution between nimodipine and the peak immediately prior tonimodipine, at RRT 0.9 (wherein RRT stands for Relative Retention Time)

Accurately weigh approximately 20 mL of sample solution into a lowactinic 50 mL volumetric flask. Add 10 mL of THF and shakemechanistically (for example, wrist-action shaker) for 5 minutes. Diluteto volume with mobile phase. Store at 4° C. Concentration isapproximately 1.2 mg/mL nimodipine.

Inject the Nimodipine Resolution Standard. For the Nimodipine ResolutionStandard, Resolution (R) between the unknown peak before nimodipine (RRT0.9) and nimodipine in the resolution solution should be not less that(NLT) 1.0 (R>=1.0). Inject the diluent solution as prescribed above postinjection of the Resolution Standard.

Inject the Nimodipine Related Compound A Working Standard six times. Thepercent relative standard deviation (% RSD) should be less than or equalto 10%. Please note that equilibration injections of the standard may beallowed post the injections of the Nimodipine Resolution standard anddiluent injections.

Inject the Nimodipine Related Compound A Check Standard Solution twotimes. Comparison of the average peak area responses (area per unitweight) (n=2) of the check standard and working standard (n=6) is ±10%.

Inject in duplicate each sample preparation and inject a standard induplicate after every six samples. Quantify the known related compoundsand any additional peaks of unknown individual impurities.

Example 2: Solubility Studies

The solubility of nimodipine in various aqueous solvent systems wasevaluated. Samples were prepared with the solvent systems shown inTables VI-IX. The individual solvents were prepared first, and thennimodipine was added incrementally and mixed using a magnetic stirrerand stir bar for at least 30 minutes at room temperature, until visualsaturation was achieved. The individual solutions were centrifuged,filtered, prepared into analytical diluent, and then injected onto theHPLC system to confirm the actual nimodipine concentration in eachsolution.

TABLE VI Nimodipine solubility in glycerin, ethanol, water, and PEG400when PEG400 is held constant Nimodipine Glycerin % Ethanol % Water %PEG400 % mg/mL 55 0.4 1 43 5.2 51 0.4 5 43 4.3 46 0.4 10 43 1.5 36 0.420 43 1.5

TABLE VII Nimodipine solubility in glycerin, ethanol, water, and PEG400when glycerin is held constant Nimodipine Glycerin % Ethanol % Water %PEG400 % mg/mL 35 0.4 1 63 13.4 35 0.4 5 59 10.0 35 0.4 10 54 5.7 36 0.420 43 1.5

TABLE VIII Nimodipine solubility in ethanol, water, and PEG400Nimodipine Glycerin % Ethanol % Water % PEG400 % mg/mL 0 1.0 10 89 31 05.0 10 85 29 0 1.0 20 79 18 0 5.0 20 75 14

TABLE IX Nimodipine solubility in water and PEG400 Nimodipine Glycerin %Ethanol % Water % PEG400 % mg/mL 0 0 1 99 43 0 0 5 95 38 0 0 10 90 26 00 15 85 14 0 0 25 75 10 0 0 40 60 1.3 0 0 50 50 0.4

TABLE X Nimodipine solubility in glycerin, water, and PEG400 when PEG400is held constant at 60% Nimodipine Glycerin % Ethanol % Water % PEG400 %mg/mL 39 0 1 60 2.1 30 0 10 60 1.6 20 0 20 60 1.5

1.-14. (canceled)
 15. A liquid composition comprising nimodipine and asolvent system from about 50% to about 97% (w/v) polyethylene glycol(PEG), about 1% to about 35% (w/v) water, from about 0.5% to about 5%(w/v) ethanol, and optionally from about 1% to about 50% (w/v) glycerin,wherein the concentration of nimodipine is about 6 mg/mL or greater orabout 12 mg/mL, and wherein about 5% or less nimodipine degradation isobserved over a period of at least six months when exposed to 40° C. and75% relative humidity.
 16. The liquid composition of claim 15, whereinthe solvent system consists of PEG, water, and ethanol.
 17. The liquidcomposition of claim 15, wherein the solvent system consists of PEG,water, ethanol, and glycerin.
 18. The liquid composition of claim 15,wherein the solvent system comprises from about 65% to about 97% (w/v)PEG.
 19. The liquid composition of claim 15, wherein the solvent systemcomprises from about 5% to about 35% (w/v) water.
 20. The liquidcomposition of claim 15, wherein the solvent system comprises from about5% to about 25% (w/v) water.
 21. The liquid composition of claim 15,wherein the solvent system comprises from about 10% to about 20% (w/v)water.
 22. The liquid composition of claim 15, wherein the solventsystem comprises from about 10% (w/v) water.
 23. The liquid compositionof claim 15, wherein the solvent system comprises from about 20% (w/v)water.
 24. The liquid composition of claim 15, wherein the solventsystem comprises from about 1% to about 5% (w/v) ethanol.
 25. The liquidcomposition of claim 15, wherein the solvent system does not compriseglycerin.
 26. The liquid composition of claim 15, wherein the solventsystem comprises from about 5% (w/v) ethanol.
 27. The liquid compositionof claim 15, wherein the solvent system comprises from about 75% toabout 90% (w/v) PEG.
 28. The liquid composition of claim 15, whereinnimodipine is present in an amount of about 60 mg per dosage unit.